Human T-cell lymphotropic virus type I (HTLV-I) is associated with two human diseases, adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). Lymphocytes from both ATL and TSP/HAM patients display abnormal proliferation properties in culture. Purified, soluble Tax1 protein can be taken up by, and stimulate proliferation of, uninfected phyto-hemagglutinin-treated human peripheral blood lymphocytes (PBLs). Tax1 was 40-70% as active as IL-2 in stimulating proliferation of PBLs. Lymphocyte proliferation can be induced at extracellular Tax1 concentrations as low as 25 pM. The proliferative response induced by extracellular Tax1 is accompanied by an activation of endogenous interleukin-2 receptor alpha chain (IL-2Ralpha) expression in human lymphocytes. Functional activation of IL-2Ralpha expression in PBLs treated with Tax1 was demonstrated using a 125I IL-2 binding assay. In addition, an ELISA assay demonstrated that soluble IL-2Ralpha in the media of IL-2 and Tax1-treated cells was over 13-fold greater than in the media of control-treated cells. Overexpression of IL-2Ralpha is a common clinical feature of some ATL and TSP/HAM patients. The ability of extracellular Tax1 protein to activate expression of IL-2Ralpha in both infected and uninfected lymphocytes may contribute to the abnormal lymphocyte proliferation observed with both ATL and TSP/HAM lymphocytes.